Abstract
BackgroundAlthough extensive studies have investigated radiation-induced injuries in particular gastrointestinal (GI) segments, a systematic comparison among the different segments on the basis of mode, magnitude and mechanism has not been reported. Here, a comparative study of segment-specific molecular and cellular responses was performed on jejunum, ileum and colon obtained at three time points (4, 7 and 12 days after irradiation) from non-human primate (Rhesus macaque) models exposed to 6.7 Gy or 7.4 Gy total body irradiation (TBI).ResultsPathway analysis on the gene expression profiles identified radiation-induced time-, dose- and segment-dependent activation of tumor necrosis factor α (TNFα) cascade, tight junction, apoptosis, cell cycle control/DNA damage repair and coagulation system signaling. Activation of these signaling pathways suggests that colon sustained the severest mucosal barrier disruption and inflammation, and jejunum the greatest DNA damage, apoptosis and endothelial dysfunction. These more pronounced alterations correlate with the high incidence of macroscopic pathologies that are observed in the colon after TBI. Compared to colon and jejunum, ileum was resistant to radiation injury. In addition to the identification a marked increase of TNFα cascade, this study also identified radiation induced strikingly up-regulated tight junction gene CLDN2 (196-fold after 7.4-Gy TBI), matrix degradation genes such as MMP7 (increased 11- and 41-fold after 6.7-Gy and 7.4-Gy TBI), and anoikis mediated gene EDA2R that mediate mucosal shedding and barrier disruption.ConclusionsThis is the first systematic comparative study of the molecular and cellular responses to radiation injury in jejunum, ileum and colon. The strongest activation of TNFα cascades and the striking up-regulation of its down-stream matrix-dissociated genes suggest that TNFα modulation could be a target for mitigating radiation-induced mucosal barrier disruption.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-2168-y) contains supplementary material, which is available to authorized users.
Highlights
Extensive studies have investigated radiation-induced injuries in particular gastrointestinal (GI) segments, a systematic comparison among the different segments on the basis of mode, magnitude and mechanism has not been reported
Apoptosis of massively DNA-damaged crypt cells prevents them from reentering the cell cycle [14], the toxins released from dead cells can cause damage to surrounding tissues, which could induce a second wave of cell death [15]
Activation of signaling cascades suggests that colon undergoes the most severe mucosal barrier interruption and inflammation and that jejunum experiences the most DNA damage and repair, apoptosis and endothelial dysfunction
Summary
Extensive studies have investigated radiation-induced injuries in particular gastrointestinal (GI) segments, a systematic comparison among the different segments on the basis of mode, magnitude and mechanism has not been reported. The GI system initiates a series of compensated signaling cascades involved in cell death, inflammation, antimicrobial responses and tissue remodelling [8, 9]. Apoptosis of massively DNA-damaged crypt cells prevents them from reentering the cell cycle [14], the toxins released from dead cells can cause damage to surrounding tissues, which could induce a second wave of cell death [15]. These events occur sequentially after radiation exposure and are governed by underlying cellular and molecular responses
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